Organocatalyzed enantioselective protonation of silyl enol ethers: Scope, limitations, and application to the preparation of enantioenriched homoisoflavones

Article abstract of DOI:10.1021/jo101585t

In the present work, enantioselective protonation of silyl enol ethers is reported by means of a variety of chiral nitrogen bases as catalysts, mainly derived from cinchona alkaloids, in the presence of various protic nucleophiles as proton source. A detailed study of the most relevant reaction parameters is disclosed allowing high enantioselectivities of up to 92% ee with excellent yields to be achieved under mild and eco-friendly conditions. The synthetic utility of this organocatalytic protonation was demonstrated during the preparation of two homoisoflavones 4a and 4b, isolated from Chlorophytum Inornatum and Scilla Nervosa, which were obtained with 81% and 78% ee, respectively.

Full text of DOI:10.1021/jo101585t

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Organocatalyzed Enantioselective Protonation of Silyl Enol Ethers:
Scope, Limitations, and Application to the Preparation of
Enantioenriched Homoisoflavones
Thomas Poisson,† Vincent Gembus,† Vincent Dalla,‡ Sylvain Oudeyer,*,† and
Vincent Levacher*,†
†
ꢀ
ꢀ
Laboratoire de Chimie Organique Bio-organique Reactivite et Analyse (COBRA),
ꢀ
ꢁ
CNRS UMR 6014 & FR 3038, Universite et INSA de Rouen, Rue Tesniere, Mont-Saint-Aignan 76130-F,
‡
France, and Laboratoire de Chimie. URCOM, EA 3221, Faculte des Sciences et Techniques de
ꢀ
l’Universite du Havre. 25, Rue Philippe Lebon BP 540, Le Havre 76058-F, France
ꢀ
vincent.levacher@insa-rouen.fr; sylvain.oudeyer@insa-rouen.fr
Received August 12, 2010
In the present work, enantioselective protonation of silyl enol ethers is reported by means of a variety of
chiral nitrogen bases as catalysts, mainly derived from cinchona alkaloids, in the presence of various
protic nucleophiles as proton source. A detailed study of the most relevant reaction parameters is
disclosed allowing high enantioselectivities of up to 92% ee with excellent yields to be achieved under mild
and eco-friendly conditions. The synthetic utility of this organocatalytic protonation was demonstrated
during the preparation of two homoisoflavones 4a and 4b, isolated from Chlorophytum Inornatum and
Scilla Nervosa, which were obtained with 81% and 78% ee, respectively.
Introduction
Since the first report of Duhamel and Plaquevent in 19762
dealing with the protonation of enolates, a wide range of
approaches have been developed including decarboxylative
protonation of keto-esters,3 protonation of photoenols,4 addi-
tion of protic nucleophiles to unsaturated carbonyl compounds5
and ketenes,6 as well as biocatalyzed protonation of enol
acetates using enzymes7 and antibodies.8 Among all these
A significant amount of research has been devoted to the
development of efficient strategies, based on enantioselective
protonation of enolates, for accessing enantiomerically en-
riched R-monosubstituted carbonyl compounds.1 From a
synthetic viewpoint, enantioselective protonation emerges
as a good alternative to asymmetric alkylation of enolates
which suffer from dialkylation side reactions. In addition,
more fundamental aspects related to asymmetric transfer of
the smallest element of the periodic table make enantio-
selective protonation a challenging stereoselective process.
(2) (a) Duhamel, L. C. R. Acad. Sci. 1976, 282, 125–127. (b) Duhamel, L.;
Plaquevent, J. C. Tetrahedron Lett. 1977, 18, 2285–2288. (c) Duhamel, L.;
Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415–7416.
(3) (a) Blanchet, J.; Baudoux, J.; Amere, M.; Lasne M.-C.; Rouden, J.
Eur. J. Org. Chem. 2008, 5493-5506 and references cited therein. (b) Mohr,
J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006,
128, 11348–11349.
*To whom correspondence should be addressed. Tel: þ33(0)235522485.
Fax:þ33(0)235522962.
(4) (a)Piva, O.; Mortezaei, R.;Henin, F.;Muzart,J.;Pete, J. P. J. Am. Chem.
Soc. 1990, 112, 9263–9272. (b) Piva, O.; Pete, J. P. Tetrahedron Lett. 1990, 31,
ꢀ
(1) For reviews, see: (a) Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566–2587.
(b) Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2010, 12, 1–24. (c)
Duhamel, L.; Duhamel, P.; Plaquevent, J. C. Tetrahedron: Asymmetry 2004, 15,
3653–3691. (d) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009,1, 359–369.
5157–5160. (c) Henin, F.; Letinois, S.; Muzart, J. Tetrahedron:Asymmetry2000,
11, 2037–2044. (d) Henin, F.; Muzart, J.; Pete, J. P.; M’Boungou-M’Passi, A.;
Rau, H. Angew. Chem., Int. Ed. 1991, 30, 416–418. (e) Henin, F.; M’Boungou-
M’Passi, A.; Muzart, J.; Pete, J. P. Tetrahedron 1994, 50, 2849–2864.
7704 J. Org. Chem. 2010, 75, 7704–7716
Published on Web 10/19/2010
DOI: 10.1021/jo101585t
r
2010 American Chemical Society

Poisson et al.
JOCArticle
strategies, enantioselective protonation of metal-enolates
has largely dominated the literature in this field, providing
efficient stoichiometric processes mainly developed by the
group of Fehr,9 Yamamoto,10 Koga,11 and Vedejs.12 The
search of catalytic processes has long remained the fore-
most challenge in this field, until this important milestone
was overcome by Fehr, who reported the first catalytic
enantioselective protonation of ketenes.13 This initial re-
port was followed soon after by a series of papers covering
either the catalytic protonation of lithium enolates14 or the
catalytic protonation of silyl enolates in the presence of
Lewis acid catalysts.15
SCHEME 1. Proposed Activation Mode of Silyl Enolate 2
by Means of a Tertiary Ammonium Ion Pair 1-HX (X = F,
RCO2, ArO)
Since then, the challenge faced by synthetic chemists has
been to develop catalytic processes under metal-free and
environmentally benign conditions. The development of
organocatalytic processes is still an important challenge in
the field of asymmetric protonation. In this environmental
context, because silicon is considered an eco-friendly element
due to its abundance and low toxicity, silyl enolates may be
regarded as the substrate of choice to address this challenge.
Organocatalytic protonation of silyl enolates has emerged
only recently as a useful synthetic tool.16 We previously
reported the first successful organocatalytic protonation of
silyl enolates by utilizing various protic nucleophiles as the
proton source in the presence of cinchona alkaloids as chiral
Brønsted bases.16a,b Herein, we present a full account of our
investigations into the scope and limitations of this organo-
catalytic strategy. Shortly afterward, Yamamoto reported
another elegant organocatalytic strategy making use of
N-triflyl thio- or selenophosphoramides as chiral Brønsted
acid catalysts in the presence of phenol.16c Surprisingly, one
should note that only a few synthetic applications involving
a catalytic enantioselective protonation have so far been
reported in the literature.9,13 To fill this gap, the efficiency
of this organocatalytic process will be demonstrated in the
stereoselective synthesis of two natural homoisoflavones.
(5) (a) Pracejus, H.; Wilcke, F. W.; Hanemann, K. J. Prakt. Chem. 1977,
319, 219–229. (b) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y.
J. Chem. Soc., Chem. Commun. 1991, 485–486. (c) Li, B. J.; Jiang, L.; Liu, M.;
Chen Y. C.; Ding L. S.; Wu, Y. Synlett 2005, 603-606. (d) Leow, D.; Tan,
C. H. Chem. Asian J. 2009, 4, 488–507. (e) Leow, D.; Lin, S.; Chittimalla,
S. K.; Fu, X.; Tan, C. H. Angew. Chem., Int. Ed. 2008, 47, 5641–5645.
(6) (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9–22. (b)
Pracejus, H.; Maetje, H. J. Prakt. Chem. 1964, 24, 195–205. (c) Pracejus,
H.; Kohl, G. Justus Liebigs Ann. Chem. 1969, 722, 1–11. (d) Blake, A. J.;
Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead, A. J. Tetrahedron
Lett. 2001, 42, 2877–2881. (e) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am.
Chem. Soc. 1999, 121, 2637–2638. (f) Hodous, B.-L.; Fu, G.-C. J. Am. Chem.
Soc. 2002, 124, 10006–10007. (g) Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 6176–6177. (h) Schaefer, C.; Fu, G. C. Angew. Chem., Int. Ed.
2005, 44, 4606–4608. (i) Dai, X.; Nakai, T.; Romero, J. A. C.; Fu, G. C.
Angew. Chem., Int. Ed. 2007, 46, 4367–4369. (j) Wang, X. N.; Lv, H.; Huang,
X. L.; Ye, S. Org. Biomol. Chem. 2009, 7, 346–350.
Results and Discussion
(7) (a) Matsumoto, K.; Tsutsumi, S.; Ihori, T.; Ohta, H. J. Am. Chem.
Soc. 1990, 112, 9614–9619. (b) Hirata, T.; Shimoda, K.; Kawano, T.
Tetrahedron: Asymmetry 2000, 11, 1063–1066. (c) Sakai, T.; Matsuda, A.;
Tanaka, Y.; Korenaga, T.; Ema, T. Tetrahedron: Asymmetry 2004, 15, 1929–
1932.
(8) (a) Fuji, I.; Lerner, R. A.; Janda, K. J. Am. Chem. Soc. 1991, 113,
8528–8529. (b) Reymond, J. L.; Janda, K.; Lerner, R. A. J. Am. Chem. Soc.
1992, 114, 2257–2258. (c) Reymond, J. L.; Janda, K.; Lerner, R. A. Angew.
Chem., Int. Ed. 1994, 33, 475–477.
(9) Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 109, 6910–6911.
(10) (a) Yanagisawa, A.; Kuribayash, T.; Kikuchi, T.; Yamamoto, H.
Angew. Chem., Int. Ed. 1994, 33, 107–109. (b) Ishihara, K.; Kaneeda, M.;
Asakawa, K.; Yamamoto., H. J. Am. Chem. Soc. 1994, 116, 11179–11180. (c)
Yanagisawa, A.; Kikuchi, T.; Kuribayashi, T.; Yamamoto, H. Tetrahedron
1998, 54, 10253–10264. (d) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 24–25.
(11) Yasukata, T.; Koga, K. Tetrahedron: Asymmetry 1993, 4, 35–38.
(12) (a) Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1991, 113, 5483–5485. (b)
Vedejs, E.; Lee, N. J. Am. Chem. Soc. 1995, 117, 891–900.
Rational Design of the Enantioselective Organocatalytic
Process. It is well-known that Lewis bases such as fluoride17
and oxanions18 activate silyl enolates through the formation
of either a “naked” enolate anion or hypervalent silicate
intermediates.19 This strong affinity of silicon for such Lewis
bases was the starting point in the design of a new organo-
catalytic process. We postulated that protonation of a chiral
tertiary amine by hydrogen fluoride, carboxylic acid, or
phenol derivatives would generate a “chiral ion pair” as the
active catalytic species wherein the anion (i.e., fluoride,
phenoxide, or carboxylate ion) would activate the silyl
enolate 2 so as to further facilitate the asymmetric transfer
of the proton from the chiral tertiary ammonium counterion
in proximity (Scheme 1).
(13) (a) Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,
1042–1044. (b) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888–
1889.
(14) For catalytic protonation of lithium enolates, see: (a) Yanagisawa,
A.; Kikuchi, T.; Watanabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995,
372–374. (b) Vedejs, E.; Kruger, A. W. J. Org. Chem. 1998, 63, 792–2793. (c)
(16) For exhaustive examples of organocatalytic enantioselective proton-
ation of silyl enolates, see: (a) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.;
Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090–7093. (b)
Poisson, T.; Oudeyer, S.; Dalla, V.; Marsais, F.; Levacher, V. Synlett 2008,
2447–2450. (c) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
6246–9247.
(17) Takashi, O.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526–533.
(18) For non exhaustive examples on the use of oxanions as Lewis base
see: (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 4050–
4051. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 5604–
5607. (c) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem.;Eur. J. 2006,
12, 5082–5093. (d) Poisson, T.; Gembus, V.; Oudeyer, S.; Marsais, F.;
Levacher, V. J. Org. Chem. 2009, 74, 3516–3519. (e) Gembus, V.; Poisson,
T.; Oudeyer, S.; Marsais, F.; Levacher, V. Synlett 2009, 2437–2440.
(19) For recent authoritative reviews on this topic, see: (a) Oestreich, M.;
Rendler, S. Synthesis 2005, 1727–1747. (b) Orito, Y.; Nakajima, M. Synthesis
2006, 1391–1401.
ꢁ
Riviere, P.; Koga, K. Tetrahedron lett. 1997, 53, 7589–7592. (d) Yamashita,
Y.; Emura, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 2000, 41, 209–213.
(e) Mitsuhashi, K.; Ito, R.; Arai, T.; Yanagisawa, A. Org. Lett. 2006, 8, 1721–
1724.
(15) For catalytic protonation of silyl enolates by means of chiral Lewis
acids, see: (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H.
J. Am. Chem. Soc. 1996, 118, 12854–12855. (b) Sugiura, M.; Nakai, T.
Angew. Chem., Int. Ed. 1997, 36, 2366–2368. (c) Nakamura, S.; Kaneeda, M.;
Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8120–8130. (d)
Yanagisawa, A.; Touge, T.; Arai, T. Angew. Chem., Int. Ed. 2005, 44, 1546–
1548. (e) Yanagisawa, A.; Touge, T.; Arai, T. Pure Appl. Chem. 2006, 78,
519–523. (f) Morita, M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858–3859.
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SCHEME 2. Postulated Catalytic Cycle for Enantioselective
Protonation of Silyl Enolate 2 by 1-HF Formed in Situ from
Benzoyl Fluoride and Ethanol
TABLE 1. Brønsted Base Screening
entry
Brønsted base
quinuclidine
conversion (%)a
time (h)
1
2
3
4
5
6
100
100b,c
100
100
87
3
3
4
20
20
20
DMAP
N-methylpyrrolidine
triethylamine
none
3
aDetermined by GC analysis. bEtOD was used instead of EtOH.
cA deuterium incorporation (>95%) was determined by 1H NMR.
(Table 2, entries 1-3), no significant enantioselectivities
were observed despite a full conversion in all cases after
12 h. Although sparteine has been found to be highly efficient
in numerous asymmetric processes, its use afforded a modest
enantiomeric excess of 9% (Table 2, entry 4).
After an extensive screening of commercially or readily
available cinchona alkaloids (Table 2, entries 5-10), dimeric
cinchona alkaloids, previously developed by Sharpless,22
showed promising results (Table 2, entries 8-10), whereas
monomeric cinchona alkaloids furnished only modest selec-
tivities (Table 2, entries 5-7). The best result was obtained
with (DHQ)2AQN, providing the corresponding 2-methyl
tetralone 3a in 42% ee (Table 2, entry 10). With (DHQ)2-
AQN selected as the best catalyst, we first paid attention
to the solvent, which proved to be a crucial parameter to
obtain an acceptable level of enantioselectivity (Table 2,
entries 10-20).
A comparable selectivity as that obtained in THF was
reproduced in dioxane (Table 2, entry 11), while the reaction
conducted in diethyl ether, chloroform, or toluene has
resulted in all cases in lower enantioselectivities (Table 2,
entries 12-14). One should notice that polar protic solvents
were detrimental to the enantioselectivity affording tetralone
3a with 20% ee in tert-amyl alcohol and as a racemic mixture
in methanol (Table 2, entries 15 and 16). The lack of
selectivity is likely due to the poor stability of silyl enolates
in alcohols, the background protonation prevailing over the
catalyzed pathway in those solvents. Finally, we were pleased
to find out that aprotic polar solvents have a beneficial effect
on the stereochemical outcome of the reaction. The use of
acetonitrile, DMF, NMP, and DMSO has provided a sig-
nificant increase of the enantioselectivity in all cases (Table 2,
entries 18-20 respectively). It is well-known that acetonitrile
and DMF are commonly used in organic silicon chemistry.
Such solvents can be viewed as neutral Lewis bases which can
coordinate to silicon resulting in further activation of the
silyl enolate. Although DMSO furnished the higher enantio-
meric excess values, its use was severely hampered by the
formation of a side product resulting from O-benzoylation of
2a with benzoyl fluoride.23 As a result, DMF offers the best
balance between good enantioselectivity and clean conver-
sion into the desired tetralone 3a.
To implement this scenario, we anticipated that hydrogen
fluoride salts 1-HF derived from a chiral amine 1 would be
very active chiral sources of protons. Quite surprisingly, such
a strategy has been completely ignored so far, probably due
to the difficulties regarding the preparation and the storage
of dry hydrogen fluoride salts 1-HF. To thwart the tricky
preparation and storage of hydrogen fluoride salts 1-HF, we
planned to use a stoichiometric mixture of acyl fluoride and
alcohol as a latent source of HF which, in the presence of a
catalytic amount of chiral tertiary amine would deliver “at
will” the required hydrogen fluoride salt 1-HF (Scheme 2).
Preliminary experiments were performed with the silyl
enolate 2a in the presence of benzoyl fluoride, ethanol, and
a catalytic amount of various Brønsted bases in THF (Table 1).
Quinuclidine and DMAP proved to be the best catalyst
candidates providing the desired 2-methyl tetralone 3a with-
in 3-4 h at room temperature (Table 1, entries 1-3), while
both N-methylpyrrolidine and triethylamine displayed much
lower reactivity (Table 1, entries 4 and 5). Interestingly, when
the reaction was carried out without nitrogen base (Table 1,
entry 6), only traces of tetralone 3a were detected after 20 h.
This suggests a good control over background reactivity
while pointing out the catalytic function of the nitrogen base
and giving strong support to the mechanism depicted in
Scheme 2. An additional labeling experiment was accom-
plished with [1D]-ethanol furnishing the corresponding [1D]-
tetralone 3a with a complete deuterium incorporation and
full conversion according to the 1H NMR analysis (Table 1,
entry 2).
At this point, we turned our attention to the search of
chiral nitrogen bases, favoring those having a pyridine or
quinuclidine scaffold (Table 2). When the reaction was
carried out with several chiral pyridine catalyst derivatives
such as Fu’s DMAP,20 Birman’s catalyst,21 or nicotine
(22) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448–
(20) Ruble, G.; Fu, G. C. J. Org. Chem. 1996, 61, 7230–7231.
(21) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. Am.
Chem. Soc. 2004, 126, 12226–12227.
451.
€
(23) Poisson, T.; Dalla, V.; Papamicael, C.; Dupas, G.; Marsais, F.;
Levacher, V. Synlett 2007, 381–386.
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JOCArticle
TABLE 2. Chiral Catalyst and Solvent Screening in Enantioselective
Protonation of Silyl Enol Ether 2aa
TABLE 3. Proton Source Screening
entry protic nucleophile X (equiv)
temp
rt
rt
rt
ee (%)a time (h)b
1
2
3
4
5
6
7
8
EtOH
2
4
1.05
1.05
1.05
2
78
71
81
81
12
12
12
20
0 °C
c
-40 °C
-
MeOH
i-PrOH
PhOH
rt
rt
rt
67
76
57
12
20
12
2
2
aDetermined by HPLC analysis using a chiral column (see the
Supporting Information). Time after which complete conversion was
b
observed from GC analysis. cLess than 5% conversion was observed.
we deemed that the proton source might also be an important
variable in the optimization of this organocatalytic process
(Table 3, entries 1 and 6-8). Although initial experiments
accomplished with ethanol as proton source afforded tetra-
lone 3a in 78% ee (Table 3, entry 1), a meaningful drop of the
selectivity was recorded with methanol providing tetralone
3a in 67% ee (Table 3, entry 6). This is likely due to a partial
alcoholysis of the silyl enolate 2a occurring more rapidly
with methanol than with ethanol. The more sterically hin-
dered isopropanol gave similar results to those obtained with
ethanol, however at the expense of the reaction time and
along with the formation of a significant amount of a side
product arising from the competitive O-benzoylation with
benzoyl fluoride23 (Table 3, entry 7). Finally, ethanol was
revealed to be the best candidate as proton source. A good
compromise between an acceptable reaction time (12 h) and
an optimal level of enantioselectivity (81% ee) could be
reached by conducting the reaction at room temperature in
the presence of 1.05 equiv of ethanol (Table 3, entries 1-5).
These reaction conditions are of particular interest with
respect to previous catalytic enantioselective protonation
reports, which usually required much lower temperatures
to reach an optimum of selectivity.
Lastly, and more interestingly from a mechanistic view-
point, is the experiment performed with phenol as proton
source (Table 3, entry 8). Indeed, although the ee values
could not be improved, the observed enantioselection may
possibly arise from a competitive pathway involving a
tertiary ammonium phenoxide as the chiral active source of
protons. Previously, quaternary ammonium phenoxide has
been reported as Lewis base catalyst in the activation of silyl
nucleophile.18c To ascertain our hypothesis, the reaction was
carried out without benzoyl fluoride, affording 2-methyl
tetralone 3a with 42% ee (Scheme 3). This result indicates
that phenols may straightforwardly generate a chiral active
proton source by simple protonation of the cinchona alka-
loid, paving the way for a substantial simplification of our
methodology presented further on.
entry
catalyst
solvent
THF
eeb (%)
abs confc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
1f
1g
1h
1i
0
0
0
9
S
S
S
S
R
S
S
S
S
S
S
S
-
24
20
27
36
39
42
45
30
26
19
20
0
1j
dioxane
diethyl ether
toluene
chloroform
tert-amyl alcohol
methanol
acetonitrile
DMF
67
78
79
84
S
S
S
S
NMP
DMSO
aThe reaction was carried out at room temperature with silyl enol
ether 2a (1 equiv), EtOH (2 equiv), PhCOF (1.05 equiv), and chiral
To gain insight into the role of the ammonium salt anion
on the enantioselectivity, benzoyl fluoride was successively
replaced by benzoyl chloride or anhydride derivatives. Thus,
benzoic or acetic anhydride led to an important decrease of
the ee values, however to a lesser extent than with acetic
anhydride, whereas benzoyl chloride furnished tetralone 3a
b
catalyst (10 mol %). Determined by HPLC using chiral column after
complete conversion (see the Supporting Information). cDetermined by
comparison with literature data.
Allowing for the fact that protic solvents exhibited a detri-
mental effect on the stereochemical outcome of the reaction,
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Poisson et al.
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SCHEME 3. Enantioselective Protonation of Silyl Enolate 2a in
the Absence of Benzoyl Fluoride
TABLE 4. Scope and Limitations of the Reaction Using a Latent
Source of HF
SCHEME 4. Influence of the Ammonium Salt Anion
SCHEME 5. Influence of the Steric Hindrance at the Silicon
Atom of the Silyl Enol Ether 2a
aDetermined by HPLC analysis using a chiral column (see the
Supporting Information). bAssigned by comparison with literature data.
d
cNot determined. Reaction was conducted at -10 °C. A 30% ee was
obtained at room temperature.
with 25% and 30% ee, respectively, albeit cyclohexanone 3q
could be isolated with an acceptable level of enantioselectivity
of 58% when conducting the reaction at -10 °C (Table 4,
entries 15 and 17). Lastly, the performance of our catalytic
process was also evaluated in the homoisoflavone series
during the protonation of silyl enolate 2p giving rise to
homoisoflavone 3p with a satisfactory ee of 68% (Table 4,
entry 16). It is noteworthy that our strategy is more per-
forming in tetralone and indanone series and complements
Yamamoto’s15a,c,16c and Yanagisawa’s15d,e catalytic ap-
proaches, both of which have proven to be mostly efficient
in cycloalkanone series while displaying lower enantioselec-
tivities in tetralone and indanone series.
Simplification of the Catalytic Process. The previous ap-
proach required the implementation of a two-component
system (PhCOF/EtOH) for the generation of dry HF, which
is accompanied by the formation of ethyl benzoate as
byproduct. At this stage, we wondered whether our metho-
dology could be made simpler to implement and more
effective in terms of atom economy. On the basis of previous
results (Table 3, entry 8), we postulated that a more readily
handy proton source such as carboxylic acid or phenol
derivatives may be employed to develop a simplified orga-
nocatalytic process. By protonation of the chiral nitrogen
base 1 with RCOOH or ArOH, one can assume a cooperative
activation of the silyl enolate 2 by the oxanion in the resulting
tertiary ammonium/oxanion ion pair 1-HX (X = RCOO,
ArO) to assist the proton transfer, as the fluoride anion did in
our previous approach (Scheme 6).
as a racemic mixture. These findings highlight the crucial role
of the fluoride anion in the ammonium salt of (DHQ)2AQN
to achieve a high level of enantioinduction (Scheme 4).
We also briefly examined the influence of steric hindrance
at the silicon atom on the outcome of the reaction (Scheme 5).
It was observed that the enantioselectivity dropped from 78%
to 66% when the reaction was carried out with the dimethyl-
chloromethylsilyl enolate 2ac, whereas the triethylsilyl enolate
2ab afforded 2-methyl tetralone 3a in 60% ee. Although the
more sterically hindered silyl enolates 2ab and 2ac yielded
somewhat lower enantiomeric excesses, their greater stabil-
ity may facilitate their storage for prolonged periods and
handling.
Scope and Limitations. With these optimized conditions in
hand, we undertook to investigate the scope of the reaction
with a variety of cyclic ketones 3a-q. Some general trends
regarding the performances of our catalytic system can be
emphasized and compared with those of earlier published
methods. As depicted in Table 4, the best enantioselectivities
could be achieved in the tetralone series reaching 92% ee
with silyl enolate 2g (Table 4, entries 1-7). Nonetheless,
one can also notice that substitution at C-6 or C-7 of the
tetralone backbone with a methoxy group affected significantly
the enantioselection of the protonation, affording tetralones
3h-k in somewhat lower enantiomeric excesses ranging from
35% to 73% (Table 4, entries 8-11). This approach still
remains an appealing strategy in indanone series, providing
enantiomeric excesses between 62% and 74% (Table 4,
entries 12-14). One can see the limitation of this method with
benzosuberone 3o and cyclohexanone 3q, which are obtained
In a first set of experiments, silyl enolate 2a was subjected to
protonation with various carboxylic acids under the optimized
reaction conditions described above, namely with (DHQ)2AQN
1j as catalyst in DMF (Table 5). In the presence of acetic or
7708 J. Org. Chem. Vol. 75, No. 22, 2010

Poisson et al.
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SCHEME 6. Simplified Organocatalytic Process by Means of
Phenol or Carboxylic Derivatives As Proton Sources
TABLE 6. Chiral Catalyst Screening
entry
catalyst
1j
X (mol %)
time (h)a
ee (%)b,c
1
2
3
4
5
6
7
8
9
10
5
2
10
10
10
10
10
10
10
14
17
12
12
12
12
12
12
66
60
57
55
32d
40
45
25
5
1i
1h
1e
1g
quinine 1k
1a
aTime after which complete conversion was observed from GC
analysis. bDetermined by HPLC using chiral column (see the Supporting
Information). cunless otherwise mentioned, S absolute configuration
was assigned by comparison with literature data. dR absolute config-
uration was assigned by comparison with literature data.
TABLE 5. Carboxylic Acid Screening
(1.05 equiv of citric acid, DMF, -10 °C, 24 h), the reaction was
carried out without catalyst 1j. In these control experiment
conditions, less than 10% of racemic tetralone 3a was obtained
providing strong evidence in favor of the postulated activation
of the silyl enolate by the carboxylate anion. However, it is
worthwhile to note that reaction temperature was found to be a
key variable in controlling the background protonation, show-
ing that a higher percentage of hydrolysis was obtained at room
temperature (i.e., 30% within 24 h).
A rapid screening of solvents revealed that DMF and
DMSO were suitable for this reaction, an enantiomeric
excess of 66% being obtained in both cases at room tem-
perature in the presence of 1j (10 mol %) and 1.05 equiv of
citric acid. All other solvents, namely CH2Cl2, CH3CN,
THF, and dioxane, were found to be inefficient due to the
solubility issue of citric acid. Finally, DMF was preferred
over DMSO for its cryogenic properties.
entry
RCO2H
X (equiv)
temp
rt
time (h)a
ee (%)b
1
2c
3
4
5
6
7
8
9
PhCO2H
AcOH
1.05
1.05
1.05
1.05
1.05
1.05
0.35
1.05
1.05
1.05
1.05
1.05
8
8
12
120
8
24
72
8
28
8
32
36
45
51
66
71
73
56
68
25
32
43
rt
0 °C
-20 °C
rt
-10 °C
-10 °C
rt
-20 °C
rt
rt
citric acid
Boc-L-proline
10
11
12
Boc-D-proline
L-tartric acid
D-tartric acid
8
8
rt
aTime after which complete conversion was observed from GC
analysis. bDetermined by HPLC analysis using a chiral column (see
the Supporting Information). c30% of hydrolysis was observed when the
reaction was conducted without catalyst at rt.
We then surveyed the performances of numerous chiral
catalysts 1 under these new simplified conditions (Table 6).
During this catalyst screening, the same trend as that pointed
out in Table 2 was observed, i.e., dimeric cinchona alkaloids
exhibited higher selectivities than their monomeric counter-
parts (Table 6, entries 1-5 vs 6-8). Among them, (DHQ)2-
AQN 1j, already previously selected as the best candidate,
emerged once again as the most effective catalyst, providing
the higher selectivities even with a catalyst loading as low as
2 mol % (Table 6, entries 1-3). The substitution of the
hydroxyl group at the C-9 position appeared to be essential
to ensure a satisfactory selectivity (Table 6, entries 6-7 vs 8).
Finally, the chiral ferrocenyl DMAP 1a was also assessed as
catalyst; although a full conversion was observed, tetralone
3a was obtained as a quasi-racemic mixture (Table 6, entry 9).
After having optimized the reaction conditions, we next
evaluated the generality of this simplified approach by using
various silyl enolates 3 and by comparing its enantioselective
performances with that making use of a latent source of
HF (Table 7). In all cases, cyclic ketones 3a-i,k,l,n,p were
obtained in excellent yields and enantioselectivities ranging
from 27% to 74% ee. As already observed with the two-
component process involving PhCOF/EtOH (Table 4), silyl
enolates of tetralone derivatives were found to afford the
benzoic acid, full protonation occurred within 8 h with modest
enantiomeric excesses of 36% and 32%, respectively (Table 5,
entries 1 and 2). When the reaction was carried out at lower
temperature, substantial improvements of the ee values
were recorded, however at the expense of the reaction time
(Table 5, entries 3 and 4). After extensive screening of a wide
range of carboxylic acids, citric acid was found to be the
best candidate (Table 5, entries 5-7). The use of 1 equiv of
citric acid at -10 °C afforded the best compromise between
selectivity and reaction time affording tetralone 3a in 71%
ee (Table 5, entry 6). Interestingly, the use of 0.35 equiv of
citric acid led to complete conversion and 73% ee, despite
an excessive reaction time (Table 5, entry 7). Using enan-
tiopure carboxylic acids (Table 5, entries 8-12), a moderate
but significant match/mismatch effect between the chiral
ammonium and the chiral carboxylate was observed,24 without
being able to improve the ee value obtained with citric acid. To
ensure that no background silyl enolate protonation through a
nonselective pathway occurred under the selected conditions
(24) For a selected example of matched/mismatched catalyst ion pair
combination, see: Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128,
13368–13369.
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Poisson et al.
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TABLE 7. Scope of the Reaction Using Citric Acid As Proton Source
TABLE 8. Phenol Derivatives Screening
entry
X
R1
R2
3
yield (%) ee (%)a abs conf b
1
2
3
4
5
6
7
8
9
(CH2)2
H
H
H
H
Me 3a
95
93
91
97
98
92
91
98
94
97
94
95
70
58
34
60
75
74
27
43
53
43
45
68
S
S
S
R
entry
R1
R2
R3
ee (%)a
time (h)
Et
F
3b
3c
1
2
3
4
5
6
7
8
9
H
H
H
CN
Me
OMe
H
H
OH
H
H
H
CN
Me
OMe
42
9
9
48
12
10
55
60
10
72
96
72
84
84
Bn 3d
ndc
nd
nd
nd
nd
S
H
H
H
H
H
H
H
5-MeO Me 3f
5-MeO Bn 3g
6-MeO Me 3h
6-MeO Bn 3i
7-MeO Bn 3k
H
H
H
32
46
20
57
65
67b
53
38
H
H
10
11
12
CH2
Me 3l
Bn 3n
Bn 3p
nd
S
OCH2
10
11
12
H
H
OMe
H
H
H
OEt
Oi-Pr
OMe
aDetermined by HPLC using chiral column (see the Supporting
Information). bAssigned by comparison with literature data. cNot
determinated.
c
-
aDetermined by HPLC using chiral column (see the Supporting
Information). b20 mol % of (DHQ)2AQN was used. cNo conversion
was observed by GC analysis
highest enantioselectivities, with the exception of 2-fluoro tetra-
lone 2c, which was obtained with 34% ee (Table 7, entries 1-8).
One can observe that both catalytic procedures follow the same
tendencies regarding the influence of the substitution pattern of
the tetralone skeleton on their enantioselective performances. In
particular, C-5-methoxy-substituted silyl enolates 2f,g gave the
highest selectivity (Table 7, entries 5 and 6), while C-6 and C-7-
methoxy-substituted silyl enol ethers 2h,i,k led to markedly
lower asymmetric inductions (Table 7, entries 7-9). Similarly,
indanones were isolated with rather modest enantioselectivities
not exceeding 45% ee (Table 7, entries 10 and 11) whereas
chromanone silyl enolate 2p afforded the corresponding ketone
3p with an acceptable 68% ee (Table 8, entry 12).
In a last attempt to improve the enantioselective perfor-
mances of this simplified approach by seeking to thwart the
background protonation observed with citric acid at room
temperature, we focused our attention on using phenols as
proton source (Table 8). As mentioned in Scheme 3, we were
pleased to observe that the reaction could proceed very
smoothly in the sole presence of phenol and (DHQ)2AQN
1j in DMF without PhCOF, affording tetralone 3a in
quantitative conversion within 2 days and a promising ee
of 42%. Furthermore, a control experiment carried out in the
absence of the catalyst clearly showed that, in contrast to
citric acid, the catalytic process is not plagued by a compe-
titive uncatalyzed background protonation at room tem-
perature. This encouraging result prompted us to screen
different phenol derivatives in the presence of (DHQ)2-
AQN 1j as catalyst in DMF at room temperature.
When using 2-hydroxyphenol (pyrocatechol), the reaction
proceeded to completion within 12 h, however to the detriment
of the enantioselectivity which dropped to 9% (Table 8, entries 1
and 2). The influence of the substitution pattern of the phenol on
the enantioselectivity follows a general trend of improving the
enantiomeric excess with the presence of electrodonating groups
(Table 8, entries 3-8), with a optimal level of enantioselection of
65% ee attained after 4 days with 4-methoxyphenol (guaiacol)
(Table 8, entry 8). Although the reaction time could be advan-
tageously reduced to 3 days by increasing the amount of catalyst
1j to 20 mol %, no improvement of the asymmetric induction
FIGURE 1. Structure of homoisoflavones 4a and 4b isolated from
Chlorophytum Inornatum and Scilla Nervosa, respectively.
was observed (Table 8, entries 8 and 9). Finally, the use of
bulkier 2-alkoxyphenols (Table 8, entries 10 and 11) or 2,20-
dimethoxyphenol (Table 8, entry 12) has a dramatic effect on
both the enantiomeric excesses and the reaction rate. Although
the use of carboxylic acid or phenol derivatives as proton
sources gives rise to more atom economic and operationally
simpler catalytic procedures than the initial strategy involving a
hydrogen fluoride salt 1-HF, the later remains more attractive
with respect to both enantioselectivities and reaction rates.
Application to the Deracemization of Two Natural Homo-
isoflavones. To illustrate the synthetic potential of this new
organocatalytic enantioselective protonation of silyl eno-
lates, we then turned our attention to the deracemization
of two natural homosioflavones 4a and 4b extracted from
Chlorophytum Inornatum and Scilla Nervosa, respectively
(Figure 1). Homoisoflavones belong to Flavonoids which
are an important class of natural product displaying various
biological properties.25 Homoisoflavone 4a first isolated by
(25) For selected examples of biological activities of homoisoflavones,
see: Siddaiah, V.; Rao, C. V.; Venkateswarlu, S.; Krishnaraju, A. V.;
Subbaraju, G. V. Bioorg. Med. Chem. 2006, 14, 2545-2551 and references
cited therein.
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SCHEME 7. Retrosynthetic Route for the Preparation of Homoisoflavones 4a and 4b
SCHEME 8. Synthesis of Homoisoflavone (rac)-4a
Gibbons et al. in 2006 from Chlorophytum Inornatum has
shown significant antibacterial activity.26 An S absolute con-
figuration was postulated by the authors by comparison of the
specific optical rotation of 4a with similar known homoiso-
flavones. To the best of our knowledge, only one racemic
synthesis has been reported in 2008 by Zhang et al.27 Homo-
isoflavone 4b was isolated from Scilla Nervosa simultaneously
and independently by Mulholland et al.28 and Abegaz et al.29 in
1999. No information about the absolute configuration of
homoisoflavone 4b has been mentioned so far in the literature.
In contrast to 4a, several racemic syntheses have already been
described;30 the synthetic racemic compound 4b was reported
to exhibit antiviral properties.31
preparation of 4b.30h Key steps of this reaction sequence
include the reduction of the double bond of 3-benzylchro-
mones 5a and 5b, respectively, obtained by cyclization of
20-hydroxy-dihydrochalcones 6a and 6b when treated with
N,N-dimethylformamide diethyl acetal (Scheme 7).
We first embarked on the synthesis of homoisoflovane
(rac)-4a, which commences with the preparation of the
o-bromophenol 7, obtained in 63% overall yield according
to a three-step reaction sequence described by Rigby et al.32
After protection of the phenol moiety as a MOM ether,
compound 8 was subjected to halogen-metal exchange
conditions to furnish the lithiated species, which was subse-
quently trapped with DMF to afford aldehyde 9 in 66% yield
from 7. The freshly prepared Grignard reagent 10 was
smoothly added to aldehyde 9 producing alcohol 11 in
75% yield, which undergoes oxidation in the presence of
PCC to afford ketone 12 in 73% yield. Acidic cleavage of the
MOM ether furnished 20-hydroxy-dihydrochalcone 6a
(86%), which was subjected to cyclization by treatment with
N,N-dimethylformamide diethyl acetal under the conditions
reported by Gomis et al.30h The resulting chromone 5a,
obtained in 71% yield, was subsequently hydrogenated over
Pd/C with ammonium formate to provide the desired race-
mic chromanone (rac)-4a in 95% yield (Scheme 8).
Both racemic homoisoflovones 4a and 4b were prepared
according to a reaction sequence partially reported for the
(26) O’Donnell, G.; Bucar, F.; Gibbons, S. Phytochemistry 2006, 67, 178–
182.
(27) Zhang, L.; Zhang, W.-G.; Kang, J.; Bao, K.; Da, Y.; Yao, X.-S.
J. Asian Nat. Prod. Res. 2008, 10, 909–913.
(28) Bangani, V.; Crouch, N. R.; Mullholland, D. A. Phytochemistry
1999, 51, 947–951.
(29) Silayo, A.; Ngadjui, B. T.; Abegaz, B. M. Phytochemistry 1999, 52,
947–955.
(30) (a) Jaspal, S.; Grover, S. K. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2004, 43, 1782–1783. (b) Davis, F. A.; Chen, B. C. Tetrahedron
Lett. 1990, 31, 6823–6826. (c) Pinkey, J. P. K.; Grover, S. K. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1986, 25, 365–367. (d) Makrandi, J. K.;
Grover., S. K. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1980,
19, 739–743. (e) Chatterjea, J. N.; Shaw, S. C.; Lal, P. K.; Singh, R. P.
J. Indian Chem. Soc. 1979, 56, 1006–1009. (f) Heller, W.; Andermatt, P.;
Schaad, W. A.; Tamm, C. Helv. Chim. Acta 1976, 59, 2048–2058. (g) Farkas,
L.; Gottsegen, A.; Nogradi, M.; Strelisky, J. Tetrahedron 1971, 5049–5054.
(h) Kirkiacharian, B. S.; Gomis, M. Synth. Commun. 2005, 35, 563–569.
(31) (a) Desideri, N.; Olivieri, S.; Stein, M. L.; Sgro, R.; Orsi, N.; Conti.,
C. Antiviral Chem. Chemother. 1997, 8, 545–555. (b) Tait, S.; Salvati, A. L.;
Desideri, N.; Fiore, L. Antiviral Res. 2006, 72, 252–255.
Homoisoflavone 4b was obtained following a similar
pathway as that described above from the commercially
available salicylaldehyde 13, which was first protected as
TBDMS ether followed by addition of the Grignard reagent
(32) (a) Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655–
12656. (b) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc.
2000, 122, 6624–6628.
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SCHEME 9. Synthesis of Homoisoflavone (rac)-4b
SCHEME 10. Deracemization of Homoisoflavones 4a and 4b by a Sequence of Silyl Enolate Formation/Enantioselective Protonation
10 to give the corresponding alcohol 15 in 74% over the two
steps. All attempts to oxidize alcohol 15 into ketone 16 using
classical methods (i.e., PCC, KMnO4, TEMPO/NaOCl,
IBX, Swern conditions) resulted in a complete degradation of
the starting material. Finally, we were pleased to find that Dess-
Martin periodinane (DMP) can be used as an effective oxidiz-
ing agent to afford ketone 16 in a moderate yield of 53%, which
after deprotection of TBDMS ether with TBAF afforded the
cyclization precursor 6b. Lastly, the desired homoisoflavone
(rac)-4b was obtained in 76% yield from 6b according to a two-
step sequence (cyclization and reduction) previously reported
in the literature (Scheme 9).30h
Both homoisoflavones (rac)-4a and (rac)-4b were then sub-
jected to a deracemization process via enantioselective proton-
ation of their corresponding silyl enolates 17a and 17b by
implementing the most efficient process using in situ generation
of HF in the presence of (DHQ)2AQN (Scheme 10). We were
pleased to obtain the enantiomerically enriched homoisofla-
vone 4a in 73% yield and 81% ee, while its analogue 4b was
isolated in comparable yield and enantioselectivity. According
to our previous observations regarding the sense of the asym-
metric induction of the protonation in the chromanone series
(Table 4, entry 16), (S)-absolute configuration was assigned in
the major enantiomer. A comparison of the optical rotations
with those of the natural products previously reported in the
literature,26,29 corroborates the (S)-configuration in the natural
homoisoflavone 4a previously postulated,26 and leads us to
suggest a (R)-absolute configuration in the natural homoiso-
flavone 4b.
alkaloid catalysts and various protic nucleophiles such as HF
(generated in situ from benzoyl fluoride and ethanol), car-
boxylic acid, or phenol derivatives. The resulting tertiary am-
monium ion pairs 1-HX (X = F, RCO2, ArO) were revealed to
be very powerful chiral protonating agents. The nature of the
anion, which is assumed to activate the silyl group to facilitate
proton delivery from the ammonium cation, proved to be a key
element in the design of this catalytic approach. Thus, high levels
of asymmetric induction (up to 92% ee) were obtained under
mild and metal-free conditions, using in situ generated HF as a
proton source. Then, a simplification of this process was devel-
oped using carboxylic acid or phenol derivatives as proton
source. Although the resulting chiral ammonium carboxylate
1-RCO2H or phenoxide 1-ArOH led to lower enantiomeric
excesses, this approach provides an important gain in terms of
atom economy and practical simplicity. An investigation of the
scope and limitations of our methodology clearly showed higher
performances in tetralone and indalone series. Then, the most
effective catalytic process (i.e., HF formed in situ by reaction of
PhCOF with EtOH) was successfully applied in the enantiose-
lective synthesis of two homoisoflavones 4a and 4b isolated
from Chlorophytum Inornatum and Scilla Nervosa. Both homo-
isoflavones 4a and 4b were obtained with good enantiomeric
excesses of 81% (7% overall yield over 12 steps) and 78% (9%
overall yield over 9 steps), respectively, highlighting the synthetic
potential of this organocatalytic strategy in a deracemization
process of bioactive R-substituted ketones.
Experimental Section
General Experimental Information. CH2Cl2, CH3CN, DMF,
DMSO, toluene, chlorotrimethylsilane, (i-Pr)2NH, and diiso-
propylamine (DIPA) were distilled from CaH2. THF, Et2O, and
dioxane were distilled from Na/benzophenone. n-BuLi (2.5 M
in hexanes) was titrated with menthol and phenantroline as
Conclusion
In summary, we have reported a full account of our investiga-
tion focusing on the development of an organocatalytic enan-
tioselective protonation by using readily available cinchona
7712 J. Org. Chem. Vol. 75, No. 22, 2010

Poisson et al.
JOCArticle
indicator prior to use. PCC was freshly prepared according to
the literature prior to use.33 Grignard reagent were prepare
according to the Gillman procedure.34 The following com-
pounds were prepared according to published procedures: silyl
enol ethers 2a,b,d,e,f,g,l,m,n,q,16a 2c,p,16b 2h,o,35 ketones 3a,b,d,
e,f,g,l,m,n,q16a and 3c,p,16b and bromo phenol 7.32b All these
1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.59 (s, 3H), 2.04
(t, 2H, J = 7.7 Hz), 2.52 (t, 2H, J = 7.7 Hz), 3.60 (s, 3H),
6.46-6.52 (m, 2H), 7.02-7.06 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ 0.7, 17.2, 28.8, 29.2, 55.3, 110.6, 113.2, 114.3, 122.8,
127.6, 137.9, 142.2, 158.2.
2-Benzyl-6-methoxy-1-trimethylsilyloxytetral-1-ene, 2i. The
titled compound was prepared according to procedure A from
ketone 3i (1.86 g, 7 mmol) and TMSCl (1 mL, 7.7 mmol)
affording the desired silyl enol ether 2i (1.75 g, 74% yield).
1
compounds gave satisfactory H and 13C NMR analyses. All
reagents were used as received unless otherwise indicated. The
NMR spectra were recorded at 300 (1H) and 75 MHz (13C) with
CDCl3 as solvent and the residual solvent (δ 7.26, 1H; δ 77.16,
13C) as internal standard unless otherwise indicated. Melting
points are uncorrected, analytical thin layer chromatographies
(TLC) were performed on a QF-254 precoated silica on alumi-
num and visualized by UV fluorescence quenching, vanilin,
KMnO4, or PMA staining. Flash chromatographies were per-
formed with silica gel (70-230 μm) unless otherwise indicated.
HPLC analyses were performed with chiral columns (4.6 mm
ꢀ25 cm) in heptane/isopropanol solvent mixtures with visuali-
zation at 254 nm (UV 1000 detector) unless otherwise stated.
Gas chromatographies were performed with a DB-5 columm
(30 m ꢀ 0.25 mm ꢀ25 μm). All experiments were conducted
under nitrogen atmosphere in oven-dried glassware with mag-
netic stirring, using standard Schlenk techniques.
Synthesis of Silyl Enol Ethers 2ab, 2ac, 2h,i,j,k,o (Procedure
A). To a solution of (i-Pr)2NH (1.19 mL, 8.4 mmol) at 0 °C in dry
THF (50 mL) was added n-BuLi (2.5 M solution in hexane,
3.22 mL, 8.05 mmol), then the whole was stirred for 15 min at
this temperature, after which the ketone 3 (7 mmol) was slowly
added at -78 °C. After 1 h at this temperature, freshly distilled
TMSCl (1 mL, 7.7 mmol) was added and the solution was
allowed to reach room temperature before being stirred for
2 h. A solution of NaHCO3 (20 mL) was added and the mixture
was extracted with Et2O (3 ꢀ 50 mL). The combined organic
layers were washed with brine and dried (MgSO4). The solvents
were removed under vacumm and the residue was purified by
flash chromatography affording the pure silyl enol ethers 2.
2-Methyl-1-triethylsilyloxytetral-1-ene, 2ab. The titled com-
pound was prepared according to procedure A from ketone 3a
(1.05 mL, 7 mmol) and TESCl (1.29 mL, 7.7 mmol) affording the
desired silyl enol ether 2ab (1.56 g, 81% yield). Colorless oil. Rf
(silica gel, 5% Et2O in cyclohexane) 0.80. 1H NMR (300 MHz,
CDCl3) δ 0.67 (q, 6H, J = 7.0 Hz), 0.97 (t, 9H, J = 7.0 Hz), 1.83
(s, 3H), 2.22 (t, 2H, J = 7.9 Hz), 2.71 (t, 2H, J = 7.9 Hz),
7.05-7.19 (m, 3H), 7.33-7.36 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ 5.5, 7.0, 17.3, 28.3, 29.3, 116.7, 121.4, 126.0, 126.2,
126.7, 134.6, 136.6, 142.8. HRMS (EI) calcd for C17H26OSi
(Mþ) 274.1753, found 274.1762.
1
Green oil. Rf (silica gel, 15% Et2O in cyclohexane) 0.75. H
NMR (300 MHz, CDCl3) δ 0.20 (s, 9H), 2.09 (t, 2H, J = 7.9 Hz),
2.68 (t, 2H, J = 7.5 Hz), 3.61 (s, 2H), 3.79 (s, 3H), 6.66 (d, 1H,
J = 2.4 Hz), 6.71-6.74 (dd, 1H, J = 8.3 Hz, J = 2.4 Hz),
7.14-7.32 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 1.0, 26.9,
29.1, 36.9, 55.6, 110.9, 113.4, 116.8, 123.7, 126.1, 127.7, 128.6,
129.1, 138.5, 140.7, 143.6, 158.8. HRMS (APIþ) calcd for
C21H27O2Si (M þ Hþ) 339.1780, found 339.1765.
2-Allyl-6-methoxy-1-trimethylsilyloxytetral-1-ene, 2j. The titled
compound was prepared according to procedure A from ketone
3j (1.51 g, 7 mmol) and TMSCl (1 mL, 7.7 mmol) affording the
desired silyl enol ether 2j (1.78 g, 88% yield). Colorless oil. Rf (silica
gel, 5% Et2O in cyclohexane) 0.88. 1H NMR (300 MHz, CDCl3) δ
0.19 (s, 9H), 2.20 (t, 2H, J = 7.9 Hz), 2.69 (t, 2H, J = 7.5 Hz), 2.99
(d, 2H, J = 6.3 Hz), 3.79 (s, 3H), 5.02-5.13 (m, 2H), 5.72-5.85
(m, 1H), 6.66-6.72 (m, 2H), 7.23-7.26 (m, 1H). 13C NMR (75
MHz, CDCl3) δ 0.7, 26.4, 28.9, 35.0, 55.3, 110.7, 113.2, 115.8,
123.3, 127.5, 136.5, 138.3, 142.9, 158.5. HRMS (APIþ) calcd for
C17H25O2Si (M þ Hþ) 289.1624, found 289.1616.
2-Benzyl-7-methoxy-1-trimethylsilyloxy-tetral-1-ene, 2k. The
titled compound was prepared according to procedure A from
ketone 3k (1.86 g, 7 mmol) and TMSCl (1 mL, 7.7 mmol)
affording the desired silyl enol ether 2k (1.75 g, 74% yield).
Colorless oil. Rf (silica gel, 10% Et2O in cyclohexane) 0.65. 1H
NMR (300 MHz, CDCl3) δ 0.23 (s, 9H), 2.09 (t, 2H, J = 8.0 Hz),
2.64 (t, 2H, J = 7.5 Hz), 3.63 (s, 2H), 3.81 (s, 3H), 6.67 (dd, 1H,
J = 8.0 Hz, J = 2.5 Hz), 6.97-7.00 (m, 2H), 7.15-7.29 (m, 5H).
13C NMR (75 MHz, CDCl3) δ 0.0, 26.2, 26.4, 36.1, 54.6, 107.2,
111.3, 119.1, 125.2, 126.8, 127.6, 127.8, 128.1, 134.7, 139.4,
142.7, 157.6. HRMS (APIþ) calcd for C21H27O2Si (M þ Hþ)
339.1780, found 339.1794.
8-Methyl-9-trimethylsilyloxy-6,7-dihydro-[5H]-benzocyclo-
heptene, 2o. The titled compound was prepared according
to procedure A from ketone 3o (1.22 g, 7 mmol) and TMSCl
(1 mL, 7.7 mmol) affording the desired silyl enol ether 2o (1.50 g,
87% yield). Colorless oil. Rf (silica gel, 5% Et2O in cyclo-
1
hexane) 0.65. H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.81
(t, 2H, J = 7.1 Hz), 1.89 (s, 3H), 2.09 (q, 2H, J = 7.1 Hz), 2.56 (t,
2H, J=7.0Hz), 7.14(m, 2H), 7.17-7.23 (m, 1H), 7.39 (d, 1H, J=
7.3 Hz). 13C NMR (75 MHz, CDCl3) δ 0.8, 18.0, 30.0, 32.9, 34.0,
118.1, 126.0, 127.1, 127.2, 128.8, 140.1, 140.3, 143.2.
2-Methyl-1-((chloromethyldimethyl)silyloxy)tetral-1-ene, 2ac.
The titled compound was prepared according to procedure A
from ketone 3a (1.06 mL, 7 mmol) and ClCH2SiMe2Cl (1 mL,
7.7 mmol) affording the desired silyl enol ether 2ac (1.40 g, 75%
yield). Colorless oil. Rf (silica gel, 5% Et2O in cyclohexane) 0.63.
1H NMR (300 MHz, CDCl3) δ 0.11 (s, 6H), 1.60 (s, 3H), 2.03 (t,
2H, J = 6.8 Hz), 2.51 (t, 2H, J = 6.8 Hz), 2.64 (s, 2H), 6.87-7.02
(m, 3H), 7.04-7.08 (m, 1H). 13C NMR (75 MHz, CDCl3) δ
-2.5, 17.5, 28.4, 29.3, 30.1, 117.8, 121.4, 126.5, 126.8, 127.2,
134.1, 136.2, 142.2. HRMS (EI) calcd for C14H19ClOSi (Mþ)
266.0894, found 266.0889.
2-Methyl-6-methoxy-1-trimethylsilyloxytetral-1-ene, 2h. The
titled compound was prepared according to procedure A from
ketone 3h (1.33 g, 7 mmol) and TMSCl (1 mL, 7.7 mmol)
affording the desired silyl enol ether 2h (1.47 g, 80% yield).
Colorless oil. Rf (silica gel, 5% Et2O in cyclohexane) 0.65.
Organocatalytic Enantioselective Protonation. Organocata-
lytic Enantioselective Protonation Mediated by PhCOF/EtOH
(Procedure B). To a solution of silyl enol ether 2 (0.5 mmol) in
dry DMF (0.5 mL) was added (DHQ)2AQN 1j (10 mol %, 43
mg, 0.05 mmol) at rt as a solution in DMF (0.5 mL) followed by
EtOH (1.05 equiv, 30 μL, 0.525 mmol) and benzoyl fluoride
(1.05 equiv, 57 μL, 0.525 mmol). The solution was stirred at this
temperature until complete disappearance of the startingmaterial
(monitored by GC/MS). The solution was diluted with Et2O and
washed with a saturated aqueous solution of NaHCO3 (10 mL),
then the aqueous layer was extracted with Et2O (3 ꢀ 10 mL). The
combined organic layers were washed with brine (3 ꢀ 25 mL) and
dried over MgSO4. The solvent was removed under vacuum and
the residue was purified by flash chromatography affording the
pure ketone 3, which was analyzed by chiral HPLC.
(33) Corey., E. J.; Suggs., J. W. Tetrahedron Lett. 1975, 2647–2650.
(34) Gilman, H.; Kirby., R. H. Org. Synth. 1925, 5, 75–77.
(35) Eames, J.; Weerasooriya, N.; Coumbarides, G. S. Eur. J. Org. Chem.
2002, 181–187.
Organocatalytic Enantioselective Protonation Mediated by
Citric Acid (Procedure C). To a solution of silyl enol ether 2
(0.5 mmol) and (DHQ)2AQN 1j (10 mol %, 43 mg, 0.05 mmol)
J. Org. Chem. Vol. 75, No. 22, 2010 7713

Poisson et al.
JOCArticle
in DMF (0.5 mL) was added citric acid (1.05 equiv, 100 mg,
0.525 mmol) at -10 °C as a solution in DMF (0.5 mL). The
reaction was stirred at -10 °C until complete disappearance of
the starting material (monitored by gas chromatography). The
solution was diluted with Et2O (10 mL), washed with a saturated
aqueous solution of NaHCO3 (10 mL) and brine (3 ꢀ 10 mL),
dried over MgSO4, and concentrated. The residue was filtered
through a short pad of silica gel (Et2O as eluent) to give the pure
ketone 3, which was analyzed by chiral HPLC.
Organocatalytic Enantioselective Protonation Mediated by
Guaiacol (Procedure D). To a solution of silyl enol ether 2
(0.5 mmol) and (DHQ)2AQN 1j (10 mol %, 43 mg, 0.05 mmol)
in DMF (0.5 mL) at rt was added guaiacol (1.05 equiv, 65 mg,
0.525 mmol) as a solution in DMF (0.5 mL). The reaction was
stirred at rt until complete disappearance of the starting material
(monitored by gas chromatography). The solution was diluted
with Et2O (10 mL), washed with a saturated aqueous solution of
NaHCO3 (10 mL) and brine (3 ꢀ 10 mL), dried over MgSO4,
and concentrated. The residue was filtered through a short pad
of silica gel (Et2O as eluent) to give the pure ketone 3, which was
analyzed by chiral HPLC.
4.87-4.91 (m, 1H), 5.27 (s, 2H), 5.92 (s, 2H), 6.58 (d, 1H, J = 8.1
Hz), 6.81-6.88 (m, 3H), 7.12 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 31.5, 38.3, 55.3, 57.4, 68.8, 97.2, 101.2, 103.6, 113.8,
119.8, 129.4, 130.0, 130.5, 134.1, 137.7, 148.5, 157.8. IR (KBr,
cm-1) 1047, 1247, 1466, 1513, 1611, 2934, 3410. Anal. Calcd for
C19H22O6: C, 65.88; H, 6.40. Found: C, 65.96; H, 6.21.
1-(2-Methoxymethyloxy-3,4-methylenedioxyphenyl)-3-(4-
methoxyphenyl)propanone, 12. To a solution of alcohol 11 (1.800 g,
5.19 mmol) in CH2Cl2 (50 mL) was added PCC (2.67 g, 10.4 mmol)
and the resulting solution was stirred for 2 h at rt. The solution was
concentrated and the residue was purified by flash chromatography
to give the corresponding ketone 12 (1.31 g, 73% yield). Colorless
oil. Rf (silica gel, 75% Et2O in petroleum ether) 0.43. 1H NMR (300
MHz, CDCl3) δ 2.95 (t, 2H, J = 8.0 Hz), 3.25 (t, 2H, J = 7.9 Hz),
3.45 (s, 3H), 3.78 (s, 3H), 5.30 (s, 2H), 6.02 (s, 2H), 6.59 (d, 1H, J =
8.3 Hz), 6.82 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.27 (d,
1H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3) δ 29.9, 45.4, 55.5,
57.8, 97.6, 102.1, 103.9, 114.1, 125.4, 127.2, 129.6, 133.8, 137.7,
139.7, 152.5, 158.1, 200.4. IR (KBr, cm-1) 1030, 1246, 1464, 1513,
1613, 1674. Anal. Calcd for C19H20O6: C, 66.27; H, 5.85. Found: C,
66.31; H, 5.96.
Synthesis of Homoisoflavone 4a. 1-Bromo-2-methoxymethy-
loxy-3,4-methylenedioxybenzene, 8. To a solution of bromo
phenol 7 (2.170 g, 10 mmol) in CH2Cl2 (50 mL) was added
DIEA (3.31 mL, 20 mmol) and MOMCl (0.911 mL, 12 mmol).
The solution was stirred for 2 h and quenched with a saturated
aqueous solution of NaHCO3 (30 mL). The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 30 mL), dried over MgSO4, and
concentrated. The residue was purified by flash chromatogra-
phy to afford the pure bromo dioxolane 8 (2.27 g, 87% yield).
Colorless oil. Rf (silica gel, 25% Et2O in petroleum ether) 0.43.
1H NMR (300 MHz, CDCl3) δ 3.66 (s, 3H), 5.37 (s, 2H), 6.04 (s,
2H), 6.55 (d, 1H, J = 8.4 Hz), 7.09 (d, 1H, J = 8.4 Hz). 13C
NMR (75 MHz, CDCl3) δ 57.5, 97.2, 102.0, 104.9, 108.1, 125.6,
137.4, 138.8, 148.9. Anal. Calcd for C9H9BrO4: C, 41.41; H,
3.47. Found: C, 41.53; H, 3.58.
1-(2-Hydroxy-3,4-methylenedioxyphenyl)-3-(4-methoxyphenyl)-
propanone, 6a. To a solution of ketone 12 (1.000 g, 2.9 mmol) in
CH2Cl2 (30 mL) was added TFA (0.432 mL, 5.8 mmol) and the
solution was allowed to stir for 1 h before being quenched with
brine. After phase separation, the organic layer was dried over
MgSO4 and concentrated to afford keto phenol 6a (749 mg, 86%
yield). White solid. Mp 94-96 °C. Rf (silica gel, 75% Et2O in
petroleum ether) 0.54. 1H NMR (300 MHz, CDCl3) δ 2.97 (t, 2H,
J = 7.8 Hz), 3.20 (t, 2H, J = 7.8 Hz), 3.78 (s, 3H), 6.04 (s, 2H), 6.43
(d, 1H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.6
Hz), 7.37 (d, 1H, J=8.5Hz). 13C NMR (75 MHz, CDCl3) δ29.52,
40.46, 55.40, 100.92, 10.78, 114.12, 116.63, 126.01, 129.49, 132.87,
134.66, 147.18, 154.01, 158.24, 204.77. IR (KBr, cm-1) 1064, 1236,
1299, 1450, 1496, 1544, 1611, 1661, 2905. Anal. Calcd for C17H16-
O5: C, 67.99; H, 5.37. Found: C, 67.85 ; H, 5.46.
2-Methoxymethyloxy-3,4-methylenedioxybenzaldehyde, 9. To
a solution of bromo dioxolane 8 (0.264 g, 1.01 mmol) in THF
(2.5 mL) was added n-BuLi (2.5 M in hexane, 0.49 mL, 1.21
mmol) at -78 °C. The solution was stirred for 15 min, then
DMF (0.234 mL, 3.03 mmol) was added and the solution was
warmed to rt before being stirred for an additional 30 min. The
solution was then quenched with NH4Cl (saturated, 5 mL) and
the aqueous layer was extracted with Et2O (2 ꢀ 20 mL). The
combined organic layers were washed with brine (30 mL), dried
over MgSO4, and concentrated. The residue was purified by
flash chromatography to afford the corresponding aldehyde 9
(172 mg, 81% yield). Colorless oil. Rf (silica gel, 25% Et20 in
3-(4-Methoxybenzyl)-7,8-methylenedioxychromen-4-one, 5a.
To a solution of keto phenol 6a (0.750 g, 2.5 mmol) in toluene
(50 mL) was added N,N-dimethylformamide diethyl acetal
(0.641 mL, 3.74 mmol) and the solution was refluxed for 10 h.
The solution was diluted with Et2O (15 mL), washed with brine
(15 mL), dried over MgSO4, and concentrated. The residue was
purified by recrystallization from dichloromethane/petroleum
ether affording chromenone 5a (551 mg, 71% yield). White
solid. Mp 121-123 °C. Rf (silica gel, 25% EtOAc in petroleum
ether) 0.29. 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 2H), 3.76 (s,
3H), 6.13 (s, 2H), 6.83 (d, 2H, J = 8.5 Hz), 6.89 (d, 1H, J = 8.5
Hz), 7.19 (d, 2H, J = 8.5 Hz), 7.49 (s, 1H), 7.77 (d, 1H, J = 8.5
Hz). 13C NMR (75 MHz, CDCl3) δ 31.04, 55.47, 103.43, 107.28,
114.22, 120.16, 120.63, 124.62, 130.23, 130.67, 134.62, 141.66,
152.22, 152.30, 158.45, 176.67. IR (KBr, cm-1) 905, 1031, 1174,
1247, 1289, 1500, 1544, 1610, 1632, 1649. Anal. Calcd for
C18H14O5: C, 69.67; H, 4.55. Found: C, 69.85; H, 4.47.
3-(4-Methoxyphenyl)-7,8-methylenedioxychroman-4-one, (rac)-4a.
To a solution of chromenone 5a (0.350 g, 1.13 mmol) in THF/
MeOH (4:1, 30 mL) were added Pd/C (10% w, 175 mg, 0.16
mmol) and HCOONH4 (2.11 g, 33.6 mmol). The resulting
solution was placed under hydrogen atmosphere (1 atm) and
heated at 50 °C for 3 h. The solution was then cooled to rt,
degassed, and filtered through a pad of Celite. The solvents
were then removed under vacuum and the residue was purified
by flash chromatography to afford the pure ketone (rac)-4a
(335 mg, 95% yield). White solid. Mp 105-106 °C. Rf (silica
gel, 60% AcOEt in petroleum ether) 0.73. 1H NMR (300 MHz,
CDCl3) δ 2.67-2.75 (m, 1H), 2.80-2.89 (m, 1H), 3.18 (dd, 1H,
J = 4.16 Hz, J = 13.6 Hz), 3.80 (s, 3H), 4.24 (dd, 1H, J = 11.4
Hz, J = 7.05 Hz), 4.41 (dd, 1H, J = 11.4 Hz, J = 4.0 Hz), 6.09
(s, 2H), 6.61 (d, 1H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.5 Hz), 7.16
1
petroleum ether) 0.21. H NMR (300 MHz, CDCl3) δ 3.49 (s,
3H), 5.33 (s, 2H), 6.01 (s, 2H), 6.60 (d, 1H, J = 8.3 Hz), 7.43 (d,
1H, J = 8.3 Hz), 10.23 (s, 1H). 13C NMR (75 MHz, CDCl3) δ
57.5, 97.2, 102.4, 104.3, 123.8, 124.9, 137.0, 142.5, 154.7, 188.1.
IR (KBr, cm-1) 925, 1275, 1349, 1473, 1615, 1681. Anal. Calcd
for C10H10O5: C, 57.14; H, 4.80. Found: C, 57.34; H, 4.86.
1-(2-Methoxymethyloxy-3,4-methylenedioxyphenyl)-3-(4-
methoxyphenyl)propanol, 11. To a solution of p-methoxy-
phenethylmagnesium chloride 10 (0.25 M in THF, 10.69 mmol)
was added aldehyde 9 (1.123 g, 5.35 mmol) as a solution in THF
(10 mL) at -78 °C. The solution was stirred for 30 min at -78 °C
before being warmed to rt and stirred for an additional 30 min at
this temperature. After adding a saturated aqueous solution of
NH4Cl(30mL), the aqueouslayerwas extracted withEtOAc (2ꢀ
50 mL) and the combined organic layers were washed with brine
(50 mL) dried over MgSO4, and concentrated. The residue was
purified by flash chromatography to give the corresponding
alcohol 11 (1.39 g, 75% yield). Colorless oil. Rf (silica gel, 50%
1
Et2O in petroleum ether) 0.23. H NMR (300 MHz, CDCl3) δ
1.96-2.17 (m, 2H), 2.58-2.76 (m, 2H), 3.45 (s, 3H), 3.78 (s, 3H),
7714 J. Org. Chem. Vol. 75, No. 22, 2010

Poisson et al.
JOCArticle
(d, 2H, J = 8.5 Hz), 7.59 (d, 1H, J = 8.4 Hz); 13C NMR (75
MHz, CDCl3) δ 32.2, 48.5, 55.6, 70.3, 103.0, 103.8, 114.4,
117.6, 123.4, 130.3, 130.5, 134.7, 145.8, 154.3, 158.7, 192.5. IR
(KBr, cm-1) 1031, 1083, 1241, 1367, 1458, 1512, 1633, 1680,
2918; HRMS (CIþ) calcd for C18H17O5 (M þ Hþ) 313.1059,
found 313.1059.
layer was extracted with CH2Cl2 (2 ꢀ 50 mL). The combined
organic layers were washed with brine (50 mL), dried over
MgSO4, and concentrated. The residue was purified by flash
chromatography to afford the corresponding ketone 16
(1.15 g, 53% yield). Colorless oil. Rf (silica gel, 10% EtOAc
1
in cyclohexane) 0.20. H NMR (300 MHz, CDCl3) δ 0.21 (s,
3-(4-Methoxybenzyl)-6-trimethylsilyloxy-[8H]-[1,3]-dioxolo-
[4,5-H]chromene, 17a. The titled compound was prepared
according to procedure A from ketone (rac)-4a (156 mg, 0.5
mmol) and TMSCl (70 μL, 0.55 mmol) affording the desired
silyl enol ether 17a (125 mg, 65% yield). Colorless oil. Rf (silica
gel, 25% Et2O in petroleum ether) 0.46. 1H NMR (300 MHz,
CDCl3) δ 0.24 (s, 9H), 3.50 (s, 2H), 3,78 (s, 3H), 4,62 (s, 2H),
5.95 (s, 2H), 6.46 (d, 1H, J = 8.1 Hz), 6.81-6.85 (m, 3H), 7.15
(d, 2H, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3) δ 0.9, 32.8,
55.5, 69.5, 101.3, 101.9, 111.2, 114.2, 116.2, 119.2, 129.7,
130.6, 134.0, 138.7, 141.1, 149.3, 158.4. HRMS (APIþ) calcd
for C21H25O5Si (M þ Hþ) 385.1471, found 385.1461.
6H), 0.95 (s, 9H), 2.89-3.05 (m, 2H), 3.00-3.05 (m, 2H), 3.73
(s, 3H), 3.77 (s, 6H), 5.98 (d, 1H, J = 1.3 Hz), 6.09 (d, 1H, J =
1.3 Hz), 6.81 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.4 Hz). 13
C
NMR (75 MHz, CDCl3) δ -4.0, 18.4, 25.9, 29.2, 47.1, 55.5,
55.6, 55.9, 91.8, 97.8, 114.0, 116.6, 129.5, 133.8, 154.1, 158.0,
158.4, 161.8, 203.9. IR (KBr, cm-1) 837, 1117, 1154, 1513,
1604, 1703, 2932. Anal. Calcd for C24H34O5Si: C, 66.94; H,
7.96. Found: C, 66.96; H, 8.15.
1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-
propanone, 6b. To a solution of ketone 16 (1.150 g, 2.67
mmol) in THF (30 mL) was added TBAF 3H2O (1.685 g,
3
5.34 mmol) and the solution was stirred for 1 h. The resulting
mixture was concentrated, diluted with EtOAc (30 mL),
washed with brine (30 mL), dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography to
afford the corresponding keto-phenol 6b (422 mg, 50% yield).
Glassy solid. 1H NMR (300 MHz, CDCl3) δ 2.94 (t, 2H, J =
7.2 Hz), 3.28 (t, 2H, J = 7.2 Hz), 3.78 (s, 3H), 3.82 (s, 3H),
3.84 (s, 3H), 5.92 (d, 1H, J = 2.3 Hz), 6.07 (d, 1H, J = 2.3 Hz),
6.85 (d, 2H, J = 8.6 Hz), 7.17 (d, 2H, J = 8.6 Hz), 14.05 (s,
1H). 13C NMR (75 MHz, CDCl3) δ 29.6, 46.2, 55.4, 55.7,
55.76, 90.9, 93.8, 105.8, 114.0, 129.5, 133.9, 158.0, 162.9,
166.1, 167.8, 204.8. IR (KBr, cm-1) 823, 1115, 1206, 1219,
1513, 1584, 1619. Anal. Calcd for C18H20O5: C, 68.34; H,
6.37. Found: C, 68.52; H, 6.58.
3-(4-Methoxyphenyl)-7,8-methylenedioxychroman-4-one, (S)-4a.
The titled compound was prepared according to procedure B from
the silyl enolate 17a (108 mg, 0.28 mmol) affording the desired
enantioenriched chromanone 4a (64 mg, 73% yield). [R]20D þ39.1
(c 0.1, CHCl3), 81% ee determined by chiral HPLC (OJ-H,
1 mL min-1, heptane/i-PrOH 8:2 v/v, retention time of both
3
enantiomers: 69.04 min (S) major and 98.52 min (R) minor).
Synthesis of Homoisoflavone 4b. 2-[(1,1-Dimethylethyl)dimethyl-
silyloxy]-4,6-dimethoxybenzaldehyde, 14. To a solution of 4,6-di-
methoxysalicylaldehyde 13 (0.322 g, 1.76 mmol) in CH2Cl2 (15 mL)
was added Et3N (0.3 mL, 2.11 mmol) and TBDMSCl (0.278 g, 1.85
mmol). The solution was stirred until complete disappearance of the
starting material. The solution was concentrated and the residue was
purified by flash chromatography to afford the corresponding
phenol silyl ether 14 (438 mg, 84% yield). Pale yellow oil. 1H
NMR (300 MHz, CDCl3) δ 0.26 (s, 6H), 1.00 (s, 9H), 3.82 (s,
3H), 3.87 (s, 3H), 5.98 (d, 1H, J = 3.0 Hz), 6.09 (d, 1H, J = 3.0 Hz),
10.34 (s, 1H). 13C NMR (75 MHz, CDCl3) δ -4.1, 18.6, 25.9, 55.9,
3-(4-Methoxybenzyl)-5,7-dimethoxychromen-4-one, 5b. To
a solution of keto-phenol 6b (0.411 g, 1.3 mmol) in toluene
(20 mL) was added N,N-dimethylformamide diethyl acetal
(0.267 mL, 1.56 mmol) and the solution was refluxed for 10 h.
The solution was diluted with Et2O (20 mL), washed with brine
(20 mL), dried over MgSO4, and concentrated. The residue was
purified by flash chromatography to afford chromenone 5b (390
mg, 92% yield). White solid. Mp 96-98 °C. Rf (silica gel, 50%
EtOAc in cyclohexane) 0.25. 1H NMR (300 MHz, CDCl3) δ 3.66
(s, 2H), 3.76 (s, 3H), 3,84 (s, 3H), 3.91 (s, 3H), 6.33 (dd, 2H, J =
2.3 Hz, J = 12.3 Hz), 6.82 (d, 2H, J = 8.6 Hz), 7.20 (d, 2H, J =
8.6 Hz), 7.34 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 31.0, 55.6,
56.0, 56.6, 92.7, 96.2, 109.7, 114.2, 126.3, 130.5, 131.3, 150.8,
158.4, 160.4, 161.4, 164.0, 176.7. IR (KBr, cm-1) 817, 1084,
1510, 1611, 1651. Anal. Calcd for C19H18O5: C, 69.93; H, 5.56.
Found: C, 70.06; H, 5.64.
3-(4-Methoxybenzyl)-5,7-dimethoxychroman-4-one, (rac)-4b.
To a solution of chromenone 5b (0.310 g, 0.95 mmol) in MeCN
(12 mL) was added Pd/C (10% w, 100 mg, 0.095 mmol) and the
solution was placed under hydrogen atmosphere (1 atm) for
2 days. The solution was degassed, filtered, and concentrated.
The residue was purified by flash chromatography to afford
dihydrochromanone (rac)-4b (259 mg, 83% yield). White solid.
Mp 81-82 °C. Rf (silicagel, 50% AcOEt inpetroleum ether) 0.48.
1H NMR (300 MHz, CDCl3) δ 2.58-2.66 (m, 1H), 2.69-2.77
(m, 1H), 3.20 (dd, 1H, J = 3.7 Hz, J = 13.3 Hz), 3.79 (s, 3H), 3.82
(s, 3H), 3.89 (s, 3H), 4.05-4.13 (m, 1H), 4.26 (dd, 1H, J = 3.8 Hz,
J = 11.2 Hz), 6.06 (m, 2H), 6.85 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H,
J = 8.6 Hz). 13C NMR (75 MHz, CDCl3) δ 32.36, 48.91, 55.61,
55.91, 56.47, 69.20, 93.31, 93.48, 105.73, 114.32, 130.47, 130.93,
158.55, 162.90, 165.26, 166.08, 191.80. IR (KBr, cm-1) 1035,
1226, 1257, 1512, 1619, 1668, 2939. HRMS (EI) calcd for
C19H20O5 (Mþ) 328.1311, found 328.1306.
56.1, 92.0, 97.9, 111.6, 161.8, 163.3, 165.9, 188.2. IR (KBr, cm-1
)
1683. Anal. Calcd for C15H24O4Si: C, 60.78; H, 8.16. Found: C,
60.62 ; H, 8.31.
1-(2-[(tert-Butyl)dimethylsilyloxy]-4,6-dimethoxyphenyl)-3-
(4-methoxyphenyl)propanol, 15. To a solution of p-methoxy-
phenetylmagnesium chloride 10 (0.25 M in THF, 108 μL, 27
mmol) at -78 °C was added aldehyde 14 (3.253 g, 10.9 mmol)
as a solution in THF (20 mL). The solution was stirred for
30 min at this temperature then warmed to rt and stirred for
30 min. The reaction mixture was quenched with NH4Cl
(saturated, 30 mL) and diluted with Et2O (30 mL). After
phase separation, the aqueous layer was extracted with Et2O
(3 ꢀ 40 mL), then the combined organic layers were washed
with brine (50 mL), dried over MgSO4, and concentrated. The
residue was purified by flash chromatography to give alcohol
15 (4 g, 85% yield). Orange oil. Rf (silica gel, 20% EtOAc in
cyclohexane) 0.40. 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 6H),
0.90 (s, 9H), 1.85-1.97 (m,1H), 2.11-2.23 (m, 1H), 2.50-2.60
(m, 1H), 2.77-2.86 (m,1H), 3.58 (d, 1H, J = 11.4 Hz), 3.76 (s,
3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.99-5.07 (m, 1H), 6.02 (d, 1H,
J = 2.2 Hz), 6.13 (d, 1H, J = 2.2 Hz), 6.80 (d, 2H, J = 8.5 Hz),
7.10 (d, 2H, J = 8.5 Hz). 13C NMR (75 MHz, CDCl3) δ -4.2,
-3.7, 18.6, 32.1, 40.0, 55.6 (2), 55.8, 68.3, 92.3, 97.7, 114.0,
115.4, 129.6, 135.0, 154.1, 157.9, 159.5, 159.9. IR (KBr, cm-1
837, 1109, 1151, 1246, 1512, 1608, 2932, 3561. Anal. Calcd for
)
C
24H36O5Si: C, 66.63; H, 8.39. Found: C, 66.78; H, 8.41.
1-(2-[(tert-Butyl)dimethylsilyloxy]-4,6-dimethoxyphenyl)-3-
(4-methoxyphenyl)propanone, 16. To a solution of alcohol 15
(2.188 g, 5.05 mmol) in CH2Cl2 (85 mL) was added Dess-
Martin periodinane (3.21 g, 7.57 mmol). The solution was
stirred for 4 h, then quenched with NaHCO3/Na2S2O3
(saturated, 1:1, 40 mL). After phase separation, the aqueous
3-(4-Methoxybenzyl)-4-trimethylsilyloxy-[8H]-[1,3]-dioxolo-
[4,5-H]chromene, 17b. The titled compound was prepared
according to procedure A from ketone (rac)-4b (164 mg, 0.5
mmol) and TMSCl (70 μL, 0.55 mmol) affording the desired
J. Org. Chem. Vol. 75, No. 22, 2010 7715

Poisson et al.
JOCArticle
silyl enol ether 17b (156 mg, 78% yield). Colorless oil. Rf (silica
gel, 40% AcOEt in petroleum ether) 0.71. 1H NMR (300 MHz,
CDCl3) δ 0.11 (s, 9H), 3.56 (s, 2H), 3.76 (s, 3H), 3.78 (s, 3H),
3.81 (s, 3H), 4.32 (s, 2H), 6.09 (s, 2H), 6.81 (d, 2H, J = 8.6 Hz),
7.15 (d, 2H, J = 8.7 Hz). 13C NMR (75 MHz, CDCl3) δ 0.6,
32.7, 55.5, 55.6 (2), 69.0, 93.3, 93.9, 106.3, 111.2, 114.1, 129.9,
131.3, 141.1, 157.3, 158.3, 158.4, 160.9. HRMS (ESIþ) calcd for
C22H29O5Si (M þ Hþ) 401.1784, found 401.1772.
time of both enantiomers: 23.03 min (S) major and 41.95 min
(R) minor).
Acknowledgment. This work was supported by CNRS,
ꢀ
University and INSA of Rouen, and the Region Haute-
Normandie. T.P. thanks the MENRT for a grant.
Supporting Information Available: General procedures for
the synthesis of racemic ketones 3, copies of 1H and 13C NMR
spectra for the compounds silyl enolates 2 and ketones 3h,i,j,k,o,
homoisoflavones 4a,b and for their synthetic precursors, and
copies of HPLC chromatograms for ketones 3h,i,j,k,o and
homoisoflavones 4a,b. This material is available free of charge
via the Internet at http://pubs.acs.org.
3-(4-Methoxybenzyl)-5,7-dimethoxychroman-4-one, (S)-4b.
The titled compound was prepared according to procedure
B from silyl enol 17b (112 mg, 0.28 mmol) affording the
desired enantioenriched chromanone 4b (75 mg, 81% yield).
[R]20 þ50.5 (c 0.5, MeOH), 78% ee determined by chiral
D
HPLC (AD-H, 1 mL min-1, heptane/i-PrOH 8:2 v/v, retention
3
7716 J. Org. Chem. Vol. 75, No. 22, 2010